Medical equipment and medical instruments that are brought into contact with blood (artificial kidneys, artificial lungs, artificial blood vessels, artificial valves, stents, stent-grafts, catheters, free-thrombus capture devices, angioscopes, sutures, blood circuits, tubes, cannulae, blood bags, syringes, and the like) are required to have high antithrombogenicity to prevent functional deterioration due to blood coagulation. In methods commonly used to impart antithrombogenicity to medical equipment and medical instruments, heparin or a heparin derivative as an anticoagulant is applied or chemically bound to a surface of a base material.
As methods of binding heparin or a heparin derivative to a surface of a base material, 1) methods in which the heparin or heparin derivative is covalently bound to a functional group introduced to the surface of the base material; and 2) methods in which the heparin or heparin derivative is bound by ionic bonding to a positively charged cationic compound introduced to the surface of the base material; are mainly known.
As methods of 1), a method in which aldehyde-modified heparin prepared by oxidation by nitrous acid treatment is covalently bound to the surface of the base material (JP 4152075 B), a method in which amino-modified heparin is bound to a cationic compound, polyethyleneimine (hereinafter referred to as “PEI”), to allow covalent bonding to the surface of the base material to which radicals are introduced (JP 3497612 B), and a method in which PEI introduced to the surface of the base material is covalently bound to heparin in the presence of a reducing agent (Japanese Translated PCT Patent Application Laid-open No. 10-513074), have been reported.
As methods of 2), methods in which, taking advantage of the fact that heparin and heparin derivatives are ionically negatively charged, heparin or a heparin derivative is bound by ionic bonding to a positively charged cationic compound have been reported (JP 60-041947 B, JP 60-047287 B, JP 4273965 B and JP 10-151192 A). Since, in antithrombogenic materials obtained by these methods, elution of the heparin or heparin derivative occurs with time, the strength of antithrombogenicity can be controlled by changing the amount of the heparin or heparin derivative bound and/or the elution rate thereof. Therefore, various combinations with positively charged cationic compounds have been studied.
For example, methods in which a surface of polyethylene terephthalate (hereinafter referred to as “PET”) or polyamide as a base material is treated with polyamine, which is a cationic compound, by aminolysis or amide formation reaction, and heparin is bound thereto by ionic bonding, to obtain an antithrombogenic material (JP 60-041947 B and JP 60-047287 B), and methods in which an ionic complex is formed between an organic cation mixture such as a quaternary ammonium salt, or a quaternary phosphonium compound, and heparin or a heparin derivative, and the resulting ion complex is dissolved in an organic solvent, followed by applying the solution to a surface of a base material, thereby obtaining an antithrombogenic material (JP 4273965 B and JP 10-151192 A), have been reported. As other methods, a method in which a polymer containing a tertiary amino group is applied to a surface of a base material, and the amino group is then modified with a quaternary ammonium, followed by binding heparin thereto by ionic bonding, thereby obtaining an antithrombogenic material (JP 3341503 B), and methods in which PEI, which is a cationic compound, is introduced to a surface of a base material by ozone treatment or plasma treatment, and heparin is then bound thereto by ionic bonding, thereby obtaining an antithrombogenic material (JP 3497612 B and JP 3834602 B), have been reported.
A method in which a negatively charged, protein non-adsorptive substance such as heparin is bound to a surface of a base material to inhibit adsorption of cells to the surface has also been reported (JP 4982752 B).
However, in the methods disclosed in JP 4152075 B, JP 3497612 B and Japanese Translated PCT Patent Application Laid-open No. 10-513074, the degree of freedom of the heparin or heparin derivative decreases due to its covalent bonding, and it is therefore difficult to obtain the antithrombogenicity required.
JP 3497612 B, Japanese Translated PCT Patent Application Laid-open No. 10-513074, JP 60-041947 B and JP 60-047287 B describe methods in which a positively charged cationic compound such as polyamine is introduced to a surface of a base material, and heparin or a heparin derivative, which is an anionic compound having anticoagulant activity, is bound to the cationic compound by ionic bonding to achieve immobilization. However, there is no description on an appropriate amount of the heparin or heparin derivative to be introduced.
In the methods disclosed in JP 4273965 B and JP 10-151192 A, an ionic complex containing heparin and the like is dissolved in an organic solvent, and the resulting solution is applied to a base material. However, the organic solvent used needs to be a solvent in which the ionic complex is soluble, while the base material is insoluble. In the drying process after application, highly hydrophilic portions in the ionic complex avoid the organic solvent to cause aggregation. Since this leads to phase separation, the solution cannot be uniformly applied to the surface of the base material at present. Moreover, covalent bonding of an organic cation mixture such as a quaternary ammonium salt, or a low-molecular-weight compound such as a quaternary phosphonium compound, to the base material does not occur only by its application. Therefore, in use as an antithrombogenic material, elution easily occurs when it is bought into contact with a body fluid such as blood, and the elution rate of the heparin or heparin derivative cannot be controlled.
JP 3341503 B, JP 3497612 B and JP 3834602 B describe methods in which a surface of a base material is coated with a cationic polymer having an amino group, and heparin is then bound to the cationic polymer by ionic bonding. However, no study has been made on an appropriate amount of the polymer to be introduced to the surface of the base material. When the amount of the polymer for coating is too small, high antithrombogenicity cannot be obtained, while when the amount is too large, the structure on the surface of the base material may be embedded.
As described in JP 4982752 B, it is conventionally known that attachment of heparin or the like to the base material leads to a decrease in adhesiveness of cells to the surface of the base material. Thus, when an antithrombogenic material using heparin or the like is used for an artificial blood vessel, stent, stent-graft, or the like, thrombosis can be prevented, but biological incorporation of the material by adhesion/growth of endothelial cells and the like may be inhibited.
In view of this, it could be helpful to provide an antithrombogenic material that is highly safe with its low hemolytic toxicity, and capable of maintaining high antithrombogenicity for a long period.
It could also be helpful to provide an antithrombogenic material that does not decrease adhesiveness of cells to the surface of the base material while the antithrombogenicity is maintained.